Pyridinic sulfonamide derivatives method of production and use thereof

ABSTRACT

New pyridinic sulfonamide derivatives represented by a general formula (I), wherein R1, represents a mono- or polyhalogenated C1-12-alkyl or a mono- or poly-halogenated C3-8-cycloalkyl group. The method of production of such derivatives and their use as active therapeutic substance in the treatment of diseases such as inflammation, arthrosis, cancer, angiogenesis and asthma are also reported.

The present invention relates to new pyridinic sulfonamides, to theirmethod of production, to pharmaceutical compositions comprising suchderivatives and their use as active therapeutic substance in thetreatment of diseases.

The new pyridinic sulfonamide derivatives, according to the invention,are represented by a general formula (I):

wherein

-   A represents a Nitrogen or a —N═O group;-   X represents Oxygen, Sulphur or an element selected from the group    consisting of (—NR₃, —CR₃R₄, —SO, —SO₂, or —CO); wherein R₃ and R₄    which can be identical or different, denotes each independently one    element selected from the group consisting of (hydrogen, a mono- or    polyhalogenated C₁₋₁₂-alkyl, a mono- or polyhalogenated    C₃₋₈-cycloalkyl, a C₁₋₁₂-alkyl or a C₃₋₈-cycloalkyl);-   R₁ represents a mono- or polyhalogenated C₁₋₁₂-alkyl, or a mono- or    poly-halogenated C₃₋₈-cycloalkyl group;-   R₂ represents a C₃₋₈-cycloalkyl group or-   an aryl group substituted or not by one or several elements selected    from the group consisting of (halogen, C₁₋₁₂-alkyl, C₃₋₈-cycloalkyl,    R₁, hydroxy, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, nitro, amino,    cyano, cyanomethyl, perhalomethyl, C₁₋₆-monoalkyl- or dialkylamino,    sulfamoyl, C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfinyl,    formyl, C₁₋₆-alkylcarbonylamino, R₅arylthio, R₅arylsulfinyl,    R₅arylsulfonyl, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkoxycarbonyl-C₁₋₆-alkyl,    carbamyl, carbamylmethyl, C₁₋₆-monoalkyl- or dialkylaminocarbonyl,    C₁₋₆-monoalkyl- or dialkylaminothiocarbonyl, ureido, C₁₋₆-monoalkyl-    or dialkylaminocarbonylamino, thioureido, C₁₋₆-monoalkyl- or    dialkylaminothiocarbonylamino, C₁₋₆-monoalkyl- or    dialkylaminosulfonyl, carboxy, carboxy-C₁₋₆-alkyl, acyl, R₅aryl,    R₅arylalkyl, R₅aryloxy),-   where R₅ denotes one or several elements selected from the group    consisting of (hydrogen, C₁₋₆-alkyl, halogen, hydroxy or    C₁₋₆-alkoxy).

“C₁₋₆-alkyl” as used herein, alone or in combination, refers to astraight or branched, saturated hydrocarbon chain having 1 to 6 carbonatoms such as methyl, propyl, butyl, isopentyl, hexyl, 1-methylbutyl,1,2-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl and thelike.

“C₁₋₁₂-alkyl” as used herein, alone or in combination, refers to astraight or branched, saturated hydrocarbon chain having 1 to 12 carbonatoms.

“C₃₋₈-cycloalkyl” as used herein refers to a radical of a saturatedcyclic hydrocarbon chain having 3 to 8 carbon atoms such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“C₁₋₆-alkoxy” as used herein, alone or in combination, refers to astraight or branched monovalent substituent comprising a C₁₋₆-alkylgroup linked through an ether oxygen having its free valence bond fromthe ether oxygen and having 1 to 6 carbon atoms such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, pentoxy, tert-butoxy and the like.

“C₁₋₆-alkoxy-C₁₋₆-alkyl” as used herein refers to a group of 2-12 carbonatoms interrupted by an oxygen atom such as —CH₂—O—CH₃, —CH₂CH₂O—CH₃,—CH₂—O—CH₂CH₃, —CH₂—CH(CH₃)₂, —CH₂CH₂—O—CH(CH₃)₂, —CH(CH₃)CH₂—O—CH₃ andthe like.

“halogen” means fluorine, chlorine, bromine or iodine.

“perhalomethyl” means trifluoromethyl, trichloromethyl, tribromomethylor triiodomethyl.

“C₁₋₆-monoalkylamino” as used herein refers to an amino group whereinone of the hydrogen atoms is substituted with a straight or branched,saturated hydrocarbon chain having 1 to 6 carbon atoms such asmethylamino, ethylamino, propylamino, isopropylamino, butylamino,tert-butylamino, isopentylamino, hexylamino and the like.

“C₁₋₆-dialkylamino” as used herein refers to an amino group wherein thetwo hydrogen atoms independently are substituted with a straight orbranched, saturated hydrocarbon chain having 1 to 6 carbon atoms such asdimethylamino, N-ethyl-N-methylamino, N-methyl-N-isopropylamino,N-butyl-N-methylamino, dihexylamino and the like.

“C₁₋₆alkylthio” as used herein, alone or in combination, refers to astraight or branched monovalent substituent comprising a C₁₋₆-alkylgroup linked through a divalent sulfur atom having its free valence bondfrom the sulfur atom and having 1 to 6 carbon atoms such as methylthio,ethylthio, propylthio, isopropylthio, butylthio, pentylthio,3-methylpentylthio and the like.

“C₁₋₆-alkylsulfonyl” as used herein refers to a monovalent substituentcomprising a C₁₋₆alkyl group linked through a sulfonyl group (—S(═O)₂—)such as methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, 2-methylpentylsulfonyland the like.

“C₁₋₆-alkylsulfinyl” as used herein refers to a monovalent substituentcomprising a C₁₋₆-alkyl group linked through a sulfinyl group (—S(═O)—)such as methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, tert-butylsulfinyl, pentylsulfinyl,2-ethylbutylsulfinyl and the like.

“acyl” as used herein refers to a monovalent substituent comprising aC₁₋₆-alkyl group linked through a carbonyl group such as acetyl,propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.

“C₁₋₆-alkylcarbonylamino” as used herein refers to an amino groupwherein one of the hydrogen atoms is substituted with an acyl group suchas acetamido, propionamido, iospopropylcarbonylamino2-ethylbutylcarbonylamino and the like.

“aryl” as used herein refers to phenyl, 1-naphthyl, or 2-naphthyl.

“arylthio” as used herein, alone or in combination, refers to an arylgroup linked through a divalent sulfur atom having its free valence bondfrom the sulfur atom, the aryl group is substituted or not by one orseveral elements of R₅ such as phenylthio, 1-naphthylthio,2-methylphenylthio, 3-methoxyphenylthio and the like.

“arylsulfinyl” as used herein, alone or in combination, refers to anaryl group linked through a sulfinyl group (—S(═O)—), the aryl group issubstituted or not by one or several elements of R₅ such asphenylsulfinyl, 2-methylphenylsulfinyl, 3-chloro-1-naphthylsulfinyl andthe like.

“arylsulfonyl” as used herein, alone or in combination, refers to anaryl group linked throug a sulfonyl group (—S(═O)₂—), the aryl group issubstituted or not by one or several elements of R₅ such asphenylsulfonyl, 2-methylphenylsulfonyl, 4-iodophenylsulfonyl,2-naphthylsulfonyl and the like.

“C₁₋₆-alkoxycarbonyl” as used herein refers to a monovalent substituentcomprising a C₁₋₆-alkoxy group linked through a carbonyl group such asmethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, 2-methylpentoxycarbonyl and the like.

“C₁₋₆-monoalkylaminocarbonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-monoalkylamino group linked through acarbonyl group such as methylaminocarbonyl, isopropylaminocarbonyl,butylaminocarbonyl, 2-methylbutylaminocarbonyl and the like.

“C₁₋₆-dialkylaminocarbonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-dialkylamino group linked through acarbonyl group such as dimethylaminocarbonyl, diethylaminocarbonylN-methyl-N-isopropylaminocarbonyl, N-methyl-N-butylaminocarbonyl,N-propyl-N-2-methylbutylaminocarbonyl and the like.

“C₁₋₆-monoalkylaminothiocarbonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-monoalkylamino group linked through athiocarbonyl group such as methylaminothiocarbonyl,isopropylaminothiocarbonyl, butylaminothiocarbonyl,3-methylpentylaminothiocarbonyl, 1,2-dimethylbutylaminothiocarbonyl andthe like.

“C₁₋₆-dialkylaminothiocarbonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-dialkylamino group linked through athiocarbonyl group such as dimethylaminothiocarbonyl,diethylaminothiocarbonyl N-methyl-N-isopropylaminothiocarbonyl,N-methyl-N-butylaminothiocarbonyl N-tert-butyl-N-hexylaminothiocarbonyland the like.

“C₁₋₆-monoalkylaminocarbonylamino” as used herein refers to an aminogroup wherein one of the hydrogen atoms is substituted with aC₁₋₆-monoalkylaminocarbonyl group such as methylaminocarbonylamino,ethylaminocarbonylamino, propylaminocarbonylamino,3-methylbutylaminocarbonylamino, 1,2-dimethylbutylaminocarbonylamino andthe like.

“C₁₋₆-dialkylaminocarbonylamino” as used herein refers to an amino groupwherein one of the hydrogen atoms is substituted with aC₁₋₆-dialkylaminocarbonyl group such as dimethylaminocarbonylamino,diethylaminocarbonylamino, N-methyl-N-ethylaminocarbonylamino,N-methyl-N-isopropylaminocarbonylamino,N-propyl-N-pentylaminocarbonylamino and the like.

“C₁₋₆-monoalkylaminothiocarbonylamino” as used herein refers to an aminogroup wherein one of the hydrogen atoms is substituted with aC₁₋₆-monoalkylaminothiocarbonyl group such asmethylaminothiocarbonlamino, ethylaminothiocarbonylamino,propylaminothiocarbonylamino, 3-methylpentylaminothiocarbonylamino andthe like.

“C₁₋₆-dialkylaminothiocarbonylamino” as used herein refers to an aminogroup wherein one of the hydrogen atoms is substituted with a C₁₋₆dialkylaminothiocarbonyl group such as dimethylaminothiocarbonylamino,diethylaminothiocarbonylamino, N-methyl-N-ethylaminothiocarbonylamino,N-methyl-N-propylaminothiocarbonylamino,N-isopropyl-N-hexylaminothiocarbonylamino,N-3-methylpentyl-N-pentylaminothiocarbonylamino and the like.

“C₁₋₆-monoalkylaminosulfonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-monoalkylamino group linked through asulfonyl group such as methylaminosulfonyl, ethylaminosulfonyl,propylaminosulfonyl, hexylaminosulfonyl, tert-butylaminosulfonyl,1,2-dimethylbutylaminosulfonyl and the like.

“C₁₋₆-dialkylaminosulfonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-dialkylamino group linked through asulfonyl group such as dimethylaminosulfonyl, diethylaminosulfonyl,N-methyl-N-ethylaminosulfonyl N-methyl-N-propylaminosulfonyl,N-hexyl-N-3-methylbutylaminosulfonyl and the like.

“ureido” as used herein means —NH—CO—NH₂.

“thioureido” as used herein means —NH—CS—NH₂.

“arylalkyl” as used herein refers to a straight or branched saturatedcarbon chain containing from 1 to 6 carbons substituted with an aromaticcarbohydride the aryl group is substituted or not by one or severalelements of R₅.

“aryloxy” as used herein refers to phenoxy, 1-naphthyloxy or2-naphthyloxy, the aryl group is substituted or not by one or severalelements of R₅.

“R₅aryl as used herein refers to aryl substituted or not by R₅.

This invention also refers to all optical isomers of pyridinicsulfonamides derivatives covered by the formula (I), particularly theoptically active isomers, and their mixtures including racemic mixturesthereof. When in the general formula (I), one has an asymetrical carbonatom, the invention refers as well to pure optical isomers than toracemic mixture.

The invention refers also to tautomeric forms of the pyridinicsulfonamide derivatives and to pharmacologically acceptable salts of thedervivatives covered by formula (I).

By pharmacologically acceptable salts of the dervivatives, one meanspharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable metal salts or optionally alkylated ammonium salts.

Preferred classes of pyridine sulfonamides derivatives according to thegeneral formula are especially those in which R₁ is trifluoromethyl.

The most preferred pyridine sulfonamide isN-(3-phenoxy-4-pyridinyl)trifluoromethanesulfonamide.

In another aspect, the invention also relates to a method of producingthe above mentioned derivatives. The method comprises the steps of

-   a) converting into pyridine N-oxide, a pyridinic compound    unsubstituted in position 4 and-   b) reacting the resulted pyridine N-oxide with a nitration reagent    to obtain a 4-nitrosubstituted pyridine N-oxide derivative.

The pyridinic compound may be any pyridinic derivative unsubstituted inposition 4 and susceptible to react with an oxydant such as H₂O₂.

The pyridinic compound unsubstituted in the 4-position may be forexample 3-bromopyridine or 3-methylpyridine as illustrated in FIGS. 1and 2.

Conversion of pyridinic compound into the pyridine N-oxyde is describedfor example in Organic Syntheses, Coll. Vol, IV, p 828, 1963.

By nitration agent one means a mixture from 1:1 to 1:2 parts ofconcentrated nitric acid and concentrated sulphuric acid to be addedbetween RT to 100° C. and under continuous stirring to the pyridineN-oxide.

The method of production of the pyridinic sulfonamide derivatives isillustrated in FIGS. 1 and 2 wherein.

FIG. 1 represents a schematic synthesis of compounds with an O, S, SO,SO₂, NR₃ and CR₃R₄ linkage and

FIG. 2 represents a schematic synthesis of compounds with a CO and CH₂linkage.

FIG. 1

The pyridine N-oxide of formula 1a may be prepared from 3-bromopyridinewhich can be oxidized using several oxidants such as H₂O₂. The nitrationat the 4-position of the pyridine N-oxide can be achieved by a mixtureof nitric and sulphuric acids to form 1b. The synthesis of 1c may berealized by reaction of 1b with a cycloalkane derivative such as acyclopentane, a cyclohexane, a cycloheptane derivative or a benzenederivative in presence of a suitable inorganic base such as K₂CO₃ orNaOH in an inert solvent such as acetonitrile or dichloromethane. Thenitropyridine N-oxide 1c is converted into the aminopyridine 1d via areduction reaction using a reductant such as iron in presence of aceticacid. For this reaction, water may be added to the mixture and thetemperature may be ranging from room temperature to the reflux of thesolvent. The synthesis of the sulfonamide 1e is completed by reaction ofthe amino-substituted pyridine derivative 1d and the appropriatesulfonyl derivative such as sulfonyl chloride, sulfonyl fluoride orsulfonic anhydride in presence of a suitable inorganic base such asK₂CO₃ or NaOH in an inert anhydrous solvent such as acetonitrile,dioxane or dichloromethane. The oxidation of 1e use an oxidant such asH₂O₂ to form 1f.

The synthesis of the sulfoxide and the sulfone family 1i and 1j isrealized throughout oxidation of the thio derivative 1c by an oxidantsuch as meta-chloroperbenzoic acid to form 1g. This oxidation isfollowed by a reduction (1 h) and the formation of the sulfonamide (1i)and finally by an oxidation (1j) of the pyridine comparable to themethods used for the preparation of 1d, 1e and 1f.

FIG. 2:

The synthesis of the ceto derivatives is achieved by the pathway ofscheme 2. This scheme begins by an oxidation of 3-methylpyridine byhydrogen peroxide in presence of acetic acid (2a). Nitration by nitricacid and sulphuric acid at the 4-position of the N-oxide lead to theformation of 2b. The methyl group of 2b is oxidized by KMnO₄ to producethe carboxylic acid 2c. The synthesis of the cyano derivative 2d isachieved in three steps. The first one is a conversion of carboxylicacid into carboxylic halide by SOCl₂. The second is the formation ofcarboxamide and the last step is a deshydration of the amide to form thenitrile 2d. The ceto linkage is prepared by reaction between 2d and anorganosmagnesium compound such as an alkyl magnesium bromide or an arylmagnesium bromide. The ceto group is then protected as an acetal byreaction of 2e and ethyleneglycol in an acidic medium. After that, thenitro group and the N-oxide of 2f is reduced by iron in presence ofacetic acid to produce 2g. This compound reacts with the appropriatesulfonyl chloride such as an alkyl or an aryl sulfonyl chloride to formthe sulfonamide 2h. The acetal may be hydrolysed to generate the cetocompound 2i. The last step is an oxidation of the pyridine 2i by H₂O₂ toform 2j. Conversion of the ceto compounds into the correspondingmethylene derivatives is achieved by a Wolff-Kishner reaction asdescribed in Organic Reactions, Vol IV, p 378, 1948.

The method of production is also illustrated by examples hereafter.

Elemental analyses (C,H,N,S) have been realised and correspond to thetheoretical formula (+/−0.4%). IR and ¹H-NMR spectra are in accordancewith proposed formulas.

The Infra-red spectra (IR) made on 1 mg of different substances havebeen recorded by means of a FT-IR Perkin Elmer 1750 and KBr pellets of250 mg.

After dissolution in DMSO-d₆, the ¹H-NMR spectrum of different moleculeshas been recorded on a Bruker 400 apparatus.

Melting points of obtained molecules have been determined on aBüchi-Tottoli apparatus.

EXAMPLE 1 Preparation ofN-(3-phenoxy-4-pyridinyl)trifluoromethane-sulfonamide (Compound 1).

Step 1: To 1.58 g of 3-bromopyridine (10 mmol) dissolved in 6 mL ofglacial acetic acid, 4 mL of 30% hydrogen peroxide are added. Thesolution is heated with reflux for 48 hours. The solvent is evaporatedunder depression. The residue is purified by column chromatography usingethyl acetate as eluent.

Yield: 64% (oil).

IR (KBr): 3109 (C—H), 1595 (C═N), 1468 (C═C), 1292 (N—O) cm⁻¹

Step 2: To 1.74 g of 3-bromopyridine N-oxide dissolved in 4 mL ofconcentrated sulphuric acid, a mixture of 4 mL of concentrated sulphuricacid and 6.7 mL of concentrated nitric acid is added under continuousstirring. The solution is heated at 90° C. for 90 minutes. Then thesolution is poured into ice and supplemented with a 50% aqueous solutionof NaOH until complete precipitation of the final compound. The yellowsolid is filtered off and washed with water to give 1.51 g of3-bromo-4-nitropyridine N-oxide.

Yield: 69%. mp: 149° C. IR (KBr): 3099 (C—H), 1589 (C═N), 1552, 1338(NO₂), 1295 (N—O), 643 (C—Br) cm⁻¹

Step 3: 4.8 mL of 10% aqueous solution of NaOH are added to 1.12 g ofphenol. After stirring for 5 minutes, water is evaporated under reducedpressure. A white solid is obtained and taken up by 10 mL ofacetonitrile and the resulting suspension is supplemented with 2.19 g of3-bromo-4-nitropyridine N-oxide. The obtained mixture is heated underreflux during 5 minutes. The mixture is further poured into ice andextracted with ethyl acetate. Organic layers are collected and driedover anhydrous magnesium sulphate. After evaporation of the solvent, asolid residue is purified by column chromatography using ethyl acetateas eluent to give 1.27 g of a yellow solid.

Yield: 54%. mp: 109° C. IR (KBr): 3109 (C—H), 1606 (C═N), 1507, 1313(NO₂), 1219 (N—O)cm⁻¹

Step 4: 2.32 g of 4-nitro-3-phenoxypyridine N-oxide dissolved in 55 mLof acetic acid and 14 mL of water are heated under reflux. Then 3.48 gof iron powder are added and the reflux is maintained for 12 hours. Thesolution is filtered and evaporated under reduced pressure. An oilyresidue is taken up with water and pH adjusted to 10 by addition of a10% aqueous solution of NaOH. The suspension is filtered and thefiltrate is extracted by ethyl acetate. Organic layers are collected anddried over anhydrous magnesium sulfate. After evaporation,4-amino-3-phenoxypyridine is obtained as a yellow oil.

Yield: 80-90%.

Step 5: To 1.81 g of 4-amino-3-phenoxypyridine dissolved in 112 mL ofdry acetonitrile are added 8.29 g anhydrous potassium carbonate. Thesuspension is stirred for 5 minutes and 2.02 mL oftrifluoromethanesulfonyl chloride are added. The mixture is stirred for12 h, then filtered and the solvent evaporated under reduced pressure.The residue is taken up with 10% aqueous solution of NaOH and the pH ofthe solution is adjusted to 5 with 1 N HCl to separate 2.53 g of a finalcompound as a white solid.

Yield: 80%; mp: 239° C.; IR (KBr): 2807, 2728, 2648 (N⁺-H), 1633 (C═N),1473 (C═C), 1343, 1129 (SO₂) cm⁻¹; NMR ¹H (DMSO-d₆): δ6.95 (d, 2H,H-2′+H-6′), 7.11 (t, 1H, H4′), 7.36 (t, 2H, H-3′+H-5′), 7.81 (d, 1H,H-5), 8.30 (d, 1H, H-6), 8.43 (s, 1H, H-2), 13,90 (bs, N—H); Anal(C₁₂H₉N₂O₃SF₃) C, H, N, S.

EXAMPLE 2 Preparation ofN-(3-(4-chlorophenoxy)-4-pyridinyl)trifluoromethanesulfonamide

Step 1 and Step 2: Similar to Example 1

Step 3: 4 mL of a 10% aqueous solution of NaOH are added to 1.4 g of4-chlorophenol. After stirring for 5 minutes, water is evaporated underreduced pressure. A white solid is obtained and taken up by 10 mL ofacetonitrile and the resulting suspension is supplemented with 2 g of3-bromo-4-nitropyridine N-oxide to obtain a mixture which is then heatedunder reflux for 5 minutes. The mixture is further filtered and thefiltrate is concentrated under reduced pressure. A solid is obtained andis dissolved in a minimum of methanol and4-nitro-3-(4-chlorophenoxy)-pyridine N-oxide is precipitated by additionof water. The precipitate is collected by filtration to give 1.15 g of ayellow solid.

Yield: 47%. mp: 101-102° C. IR (KBr): 3117, 3029 (C—H), 1610 (C═N), 1213(N—O), 1100 cm⁻¹

Step 4: 0.37 g of 4-nitro-3-(4-chlorophenoxy)-pyridine N-oxide dissolvedin 9 mL of acetic acid and 2 mL of water are heated under reflux. Tosuch warm solution are added 0.5 g of iron powder and the reflux ismaintained for 1 hour. A suspension is obtained and filtered and thefiltrate is evaporated under reduced pressure. An oily residue isobtained and taken up with water and pH adjusted to 10 by addition of a10% aqueous solution of NaOH. The resulting suspension is filtered andthe filtrate is extracted by ethyl acetate. Organic layers are collectedand dried over anhydrous magnesium sulfate. After evaporation,4-amino-3-(4-chlorophenoxy)pyridine is obtained as a yellow oil.

Yield: 80-90%.

Step 5: To 0.56 g of 4-amino-3-(4-chlorophenoxy)pyridine dissolved in 20mL of dry acetonitrile is added 1 g of anhydrous potassium carbonate.The suspension is stirred for 5 minutes and 0.794 mL oftrifluoromethanesulfonyl chloride are added. The mixture is stirred for15 minutes, then filtered and the filtrate concentrated under reducedpressure. The residue is taken up with a 10% aqueous solution of NaOHand the pH of the solution is adjusted to 7 with 1 N HCl to separate0.61 g of the final compound as a white solid which is filtered, washedwith water and dried.

Yield: 68%; mp: 222-223° C.; IR (KBr): 2810, 2732, 2648 (N⁺-H), 1636(C═N), 1474 (C═C), 1344, 1130 (SO₂) cm⁻¹.

EXAMPLE 3 Preparation ofN-(3-(3,5-dichlorophenoxy)-4-pyridinyl)trifluoromethanesulfonamide

Step 1 and Step 2: Similar to Example 1

Step 3: 4.32 mL of a 10% aqueous solution of NaOH are added to 1.76 g of3,5-dichlorophenol. After stirring for 5 minutes, water is evaporatedunder reduced pressure. A white solid is obtained and taken up by 10 mLof acetonitrile and the suspension is supplemented with 2 g of3-bromo-4-nitropyridine N-oxide and then heated under reflux for 20hours. The mixture is filtered and the filtrate is concentrated underreduced pressure. A solid is obtained and is suspended in a minimum ofcold methanol and 4-nitro-3-(3,5-dichlorophenoxy)pyridine N-oxide iscollected by filtration to give 1.25 g of a yellow final solid.

Yield: 47%. mp: 160-161° C. IR (KBr): 3051, 3014 (C—H), 1610 (C═N),1584, 1309 (NO₂), 1227 (N—O)cm⁻¹

Step 4: 0.95 g of 4-nitro-3-(3,5-dichlorophenoxy)pyridine N-oxidedissolved in 18 mL of acetic acid and 5 mL of water are heated underreflux. To the warm solution are added 1.12 g of iron powder and thereflux is maintained for 12 hours. The solution is filtered and thefiltrate is evaporated under reduced pressure. An oily residue isobtained and taken up with water and the pH adjusted to 10 by additionof a 10% aqueous solution of NaOH. The suspension is filtered and thefiltrate is extracted by ethyl acetate. Organic layers are collected anddried over anhydrous magnesium sulfate. After evaporation,4-amino-3-(3,5-dichlorophenoxy)pyridine is obtained as a yellow oil.

Yield: 80-90%.

Step 5: To 0.45 g of 4-amino-3-(3,5-dichlorophenoxy)pyridine dissolvedin 20 mL of dry acetonitrile are added 0.73 g anhydrous potassiumcarbonate. The suspension is stirred for 5 minutes and 0.551 mL oftrifluoromethanesulfonyl chloride are added. The mixture is stirred for30 minutes, then filtered and the filtrate concentrated under reducedpressure. A residue is obtained and taken up with a 10% aqueous solutionof NaOH and the pH of the solution is adjusted to 7 with 1 N HCl toseparate 0.33 g of the final compound as a white solid which isfiltered, washed with water and dried.

Yield: 49%; mp: 219-220° C.; IR (KBr): 2921, 2820, 2653 (N⁺-H), 1633(C═N), 1486 (C—C), 1344, 1126 (SO₂) cm⁻¹.

EXAMPLE 4 Preparation ofN-(3-(4-bromophenoxy)-4-pyridinyl)trifluoromethanesulfonamide

Step 1 and Step 2: Similar to Example 1

Step 3: 5.5 mL of a 10% aqueous solution of NaOH are added to 1.88 g of4-bromophenol. After stirring for 5 minutes, water is evaporated underreduced pressure. A white solid is obtained and taken up by 10 mL ofacetonitrile and the suspension is supplemented with 2 g of3-bromo-4-nitropyridine N-oxide and then heated under reflux 5 minutes.The mixture is filtered and the filtrate is evaporated under reducedpressure. A solid is obtained and is dissolved in a minimum of methanoland 4-nitro-3-(4-bromophenoxy)-pyridine N-oxide is precipitated byaddition of water. The precipitated is collected by filtration, washedwith water and dried, to give 0.96 g of a yellow solid.

Yield: 34%. mp: 124-125° C. IR (KBr): 3106 (C—H), 1605 (C═N), 1565, 1312(NO₂), 1212 (N—O)cm⁻¹

Step 4: 3 g of 4-nitro-3-(4-bromophenoxy)-pyridine N-oxide dissolved in72 mL of acetic acid and 18 mL of water are heated under reflux. To thewarm solution are added 4.2 g of iron powder and the reflux ismaintained for 12 hours. The solution is filtered and the filtrate isevaporated under reduced pressure. Oily residue is obtained and is takenup with water and the pH adjusted to 10 by addition of a 10% aqueoussolution of NaOH. The suspension is filtered and the filtrate isextracted by ethyl acetate. Organic layers are collected and dried overanhydrous magnesium sulfate. After evaporation,4-amino-3-(4-bromophenoxy)-pyridine is obtained as a yellow oil.

Yield: 80-90%.

Step 5: To 0.2 g of 4-amino-3-(4-bromophenoxy)-pyridine dissolved in 20mL of dry acetonitrile are added 2.25 g anhydrous potassium carbonate.

The suspension is stirred for 5 minutes and 0.235 mL oftrifluoromethanesulfonyl chloride are added. The mixture is stirred for1 hour, then filtered and the filtrate concentrated under reducedpressure. A residue is taken up with a 10% aqueous solution of NaOH andthe pH of the solution is adjusted to 7 with 1 N HCl to separate 0.21 gof the final compound as a white solid.

Yield: 70%; mp: 245-246° C.; IR (KBr): 2809, 2732, 2648 (N⁺-H), 1635(C═N), 1473 (C═C), 1344, 1130 (SO₂) cm⁻¹.

EXAMPLE 5 Preparation ofN-(3-(3-chlorophenoxy)-4-pyridinyl)trifluoromethanesulfonamide

Step 1 and Step 2: Similar to Example 1

Step 3: 4 mL of a 10% aqueous solution of NaOH are added to 1.4 g of3-chlorophenol. After stirring for 5 minutes, water is evaporated underreduced pressure. A white solid is obtained and taken up by 40 mL ofacetonitrile and the suspension is supplemented with 2 g of3-bromo-3-nitropyridine N-oxide and then heated under reflux for 5minutes. The mixture is filtered and the filtrate is concentrated underreduced pressure. A solid is obtained and is dissolved in a minimum ofcold methanol and 4-nitro-3-(3-chlorophenoxy)-pyridine N-oxide iscollected by filtration to give 1.06 g of a yellow solid.

Yield: 42%. mp: 105-106° C. IR (KBr): 3056 (C—H), 1604 (C═N), 1568, 1318(NO₂), 1219 (N—O)cm⁻¹

Step 4: 1 g of 4-nitro-3-(3-chlorophenoxy)-pyridine N-oxide dissolved in20 mL of acetic acid and 6 mL of water are heated under reflux. To thewarm solution are added 2.98 g of iron powder and then heated underreflux for 3 hours. The suspension is filtered and the filtrate isconcentrated under reduced pressure. Oily residue is obtained and takenup with water and the pH adjusted to 10 by addition of a 10% aqueoussolution of NaOH. The suspension is filtered and the filtrate isextracted by ethyl acetate. Organic layers are collected and dried overanhydrous magnesium sulfate. After evaporation,4-amino-3-(3-chlorophenoxy)pyridine is obtained as a yellow oil.

Yield: 90%.

Step 5: To 0.2 g of 4-amino-3-(3-chlorophenoxy)pyridine dissolved in 15mL of dry dichloromethane are added 0.5 mL of triethylamine. Thesolution is stirred for 5 minutes and 0.19 mL oftrifluoromethanesulfonyl chloride are added. The mixture is stirred for12 h, then filtered and the filtrate concentrated under reducedpressure. The residue is taken up with a 10% aqueous solution of NaOHand the pH of the solution is adjusted to 7 with 1N HCl to separate 0.2g of the final compound as a white solid which is filtered, washed withwater and dried.

Yield: 73%; mp: 198-199° C.; IR (KBr): 2896, 2815, 2650 (N⁺-H), 1632(C═N), 1473 (C═C), 1343, 1129 (SO₂) cm⁻¹.

EXAMPLE 6 Preparation ofN-(3-thiophenoxy-4-pyridinyl)trifluoromethanesulfonamide

Step 1 and Step 2: Similar to Example 1

Step 3: 2 mL of thiophenol is dissolved in 80 mL of toluene. 2.5 g ofK₂CO₃ is added and the suspension is heated until reflux occur. Then, 4g of 3-bromo-4-nitropyridine N-oxide is added and the reflux ismaintained for 2 hours. The mixture is filtered and the filtrate isconcentrated under reduced pressure. A residue is taken up by a minimumof cold ethanol and 4-nitro-3-thiophenoxypyridine N-oxide is collectedby filtration to give 2.52 g of a yellow solid.

Yield: 55%. mp: 147-148° C. IR (KBr): 3065 (C—H), 1588 (C═N), 1548, 1329(NO₂), 1230 (N—O)cm⁻¹

Step 4: 0.5 g of 4-nitro-3-thiophenoxypyridine N-oxide dissolved in 20mL of glacial acetic acid are heated under reflux. To the warm solutionare added 0.37 g of iron powder and the reflux is maintained for 2hours. The solution is filtered and the filtrate concentrated underreduced pressure. Oily residue is obtained and taken up with water andthe pH adjusted to 10 by addition of a 10% aqueous solution of NaOHsolution. The suspension is filtered and the filtrate is extracted byethyl acetate. Organic layers are collected and dried over anhydrousmagnesium sulfate. After evaporation, 4-amino-3-thiophenoxypyridine isobtained as a yellow oil.

Yield: 90%.

Step 5: To 0.45 g of 4-amino-3-thiophenoxypyridine dissolved in 20 mL ofdry acetonitrile are added 1.84 g anhydrous potassium carbonate. Thesuspension is stirred for 5 minutes and 0.47 mL oftrifluoromethanesulfonyl chloride are added. The mixture is stirred for4 h, then filtered and acetonitrile is evaporated under reducedpressure. The residue is taken up with a 10% aqueous solution of NaOHand the pH of the solution is adjusted to 5 with 1 N HCl to separate0.36 g of the final compound as a white solid which is filtered, washedwith water and dried.

Yield: 50%; mp: 188-189° C.; IR (KBr): 2807, 2728, 2648 (N⁺-H), 1633(C═N), 1473 (C═C), 1343, 1129 (SO₂

The invention also refers to the use of the pyridinic sulfonamidesderivatives covered by formula (1) and their salts for drug manufacturefor treatment and/or prevention of diseases such as inflammation,arthrosis, cancer, angiogenesis and asthma and for other pathologies inwhich they can play a role of COX-2 selective inhibitor.

Prostaglandins (PG) are key mediators involved in the inflammationprocesses. According to Bergström, S.; Ryhage, R.; Samuelsson, B.;Sjövall, J. in J. Bio. Chem., 1963, 238, 3555-3563. prostaglandins aresynthesized by cyclooxygenases (COXs) from arachidonic acid.

Different classes of anti-inflammatory drugs on the market inhibit thesynthesis of PG by inhibiting those enzymes.

The COX enzymes exist under two distinct isoforms. COX-1 is aconstitutive enzyme responsible for physiological production of PG. Thisenzyme is involved in several homeostatic processes and is thusconsidered as a “house keeping” enzyme. In contrast, COX-2 is aninducible enzyme which is mainly produced during inflammation processes.Furthermore, according to Crofford L., Lipsky P., Brooks P., AbramsonS., Simon L., van de Putte L. in. Arthritis Rheum., 2000, 43, 4-13,COX-2 is expressed during different pathologies such as arthrosis,angiogenesis and asthma.

A problem with the inhibition of COX-1 by common non-steroidalanti-inflammatory drugs (NSAID) is its side effects such as gastriculceration.

The present invention deals with the use of new COX-2 selectiveinhibitors represented by the pyridinic sulfonamide derivativesdescribed above. Such new COX-2 selective inhibitors advantageously doesnot exhibit such side effects.

The pyridinic sulfonamide derivatives described above have beenevaluated as COX inhibitors on one in vitro test and on one in vivotest. For the in vitro assay the methodology is described by X. deLeval, J. Delarge, P. Devel, P. Neven, C. Michaux, B. Masereel, B.Pirotte, J.-L. David, Y. Henrotin, J.-M. Dogné. in Prostaglandins,Leukot., Essent. Fatty Acids, 2001, 64, 211-216.

Pharmacological evaluations ofN-(3-phenoxy-4-pyridinyl)trifluoro-methanesulfonamide (compound 1) arerecorded in

Table 1 which describes Estimated IC₅₀ for compound 1 on whole bloodassay IC₅₀ IC₅₀ COX-1 COX-2 IC₅₀ COX-1/ compound (μM) (μM) IC₅₀ COX-2 12.2 0.4 5.28

The activity of the derivatives has also been evaluated by using a ratpaw oedema pharmacological model.

In Carrageenin-induced rat paw oedema model, Wistar rats were used. Themean weight of the animals was 250 g. The animals were treated with anintraperitoneal injection of the drug at the appropriate concentration(solution at the concentration of 10 mg/mL in DMSO). Lambda carrageenin(0.1 mL; 1%) was injected one hour later in the plantar region of theright hand paw. Three hours thereafter, the rats were euthanasied byinjection of nembutal (100 mg/kg) and the paws were cutted at the ankle.The swelling was calculated as a percentage increase in the weight ofthe control paw. TABLE 2 reports the effect of compound 1 on rat pawoedema compound 5 (mg/kg) 10 (mg/kg) 30 (mg/kg) Control 1 101.0 ± 8.174.7 ± 7.2 54.1 ± 17.5 96 ± 8.7

Results are expressed as percentage of growth of the paw after injectionof carrageneen (mean±standard deviation, n=6).

Those tables clearly show that compound 1 is active as COX-2 inhibitorand presents an anti-inflammatory effect in vivo.

The invention also refers to a Pharmaceutical composition comprising apyridinic sulfonamide derivative or a pharmaceutical acceptable saltthereof with a pharmaceutical acceptable acid or base, or any opticalisomer or mixture of optical isomers, including a racemic mixture or anytautomeric form together with one or more acceptable carriers ordiluents.

The pharmaceutical composition may be in a form of an oral dosage unitor parenteral dosage unit.

1. Pyridinic sulfonamide derivatives represented by a general formula(I):

wherein A represents a Nitrogen or a —N═O group; X represents Oxygen,Sulphur or an element selected from the group consisting of (—NR₃,—CR₃R₄, —SO, —SO₂, or —CO); wherein R₃ and R₄ which can be identical ordifferent, denotes each independently one element selected from thegroup consisting of (hydrogen, a mono- or polyhalogenated C₁₋₁₂-alkyl, amono- or polyhalogenated C₃₋₈-cycloalkyl, a C₁₋₁₂-alkyl or aC₃₋₈-cycloalkyl); R₁ represents a mono- or polyhalogenated C₁₋₁₂-alkylor a mono or poly-halogenated C₃₋₈-cycloalkyl group; R₂ represents aC₃₋₈-cycloalkyl group or an aryl group substituted or not by one orseveral elements selected from the group consisting of (halogen,C₁₋₁₂-alkyl, C₃₋₈-cycloalkyl, R₁, hydroxy, C₁₋₆-alkoxy,C₁₋₆-alkoxy-C₁₋₆-alkyl, nitro, amino, cyano, cyanomethyl; perhalomethyl,C₁₋₆-monoalkyl- or dialkylamino, sulfamoyl, C₁₋₆-alkylthio,C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfinyl, formyl, C₁₋₆-alkylcarbonylamino,R₅arylthio, R₅arylsulfinyl, R₅arylsulfonyl, C₁₋₆-alkoxycarbonyl,C₁₋₆-alkoxycarbonyl-C₁₋₆-alkyl; carbamyl; carbamylmethyl;C₁₋₆-monoalkyl- or dialkylaminocarbonyl, C₁₋₆-monoalkyl- ordialkylaminothiocarbonyl, ureido, C₁₋₆-monoalkyl- ordialkylaminocarbonylamino, thioureido, C₁₋₆-monoalkyl- ordialkylaminothiocarbonylamino, C₁₋₆-monoalkyl- or dialkylaminosulfonyl,carboxy, carboxy-C₁₋₆-alkyl, acyl, R₅aryl, R₅arylalkyl, R₅aryloxy) whereR₅ denotes one or several elements selected from the group consisting of(hydrogen, C₁₋₆-alkyl, halogen, hydroxy or C₁₋₆-alkoxy).
 2. Pyridinicsulfonamide derivatives according to claim 1 characterised in that R₁ istrifluoromethyl.
 3. Pyridinic sulfonamide derivatives according to claim2 characterised in that A is Nitrogen, X is oxygen, R₁ istrifluoromethyl and R₂ is phenyl.
 4. Pyridinic sulfonamide derivativesaccording to claim 1 which acts as COX-2 selective inhibitor.
 5. Amethod of producing the Pyridinic sulfonamide derivatives according toclaim 1 comprising the steps of a) converting into a pyridine N-oxide, apyridinic compound unsubstituted in position 4 and b) reacting theresulted pyridine N-oxide with a nitration reagent to obtain a4-nitrosubstituted pyridine N-oxide derivative.
 6. Pyridinic sulfonamidederivatives according to claim 1, or a pharmaceutically acceptable saltthereof with a pharmaceutically acid or base or any optical isomer ormixture of optical isomers, including a racemic mixture, or anytautomeric form for its use as active substance in drugs;
 7. Pyridinicsulfonamide derivatives according to claim 1, or a pharmaceuticallyacceptable salt thereof with a pharmaceutically acid or base or anyoptical isomer or mixture of optical isomers, including a racemicmixture, or any tautomeric form for its use in the treatment ofinflammation.
 8. Pharmaceutical composition comprising a Pyridinicsulfonamide derivative according to claim 1 or a pharmaceuticalacceptable salt thereof with a pharmaceutical acceptable acid or base,or any optical isomer or mixture of optical isomers, including a racemicmixture or any tautomeric form together with one or more acceptablecarriers or diluents.
 9. Pharmaceutical composition according to claim 8in a form of an oral dosage unit or parenteral dosage unit.
 10. Methodof treating and/or preventing diseases such as inflammation comprisingadministering an effective amount of the pharmaceutical compositionaccording to claim
 8. 11. Use of a Pyridinic sulfonamide derivativeaccording to claim 1 or a pharmaceutically acceptable salt thereof witha pharmaceutically acid or base or any optical isomer or mixture ofoptical isomers, including a racemic mixture, or any tautomeric form asa medicament.
 12. Use of a Pyridinic sulfonamide derivative according toclaim 1 for preparing a medicament.